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ORC-13661 protects sensory hair cells from aminoglycoside and cisplatin ototoxicity
journal contribution
posted on 2023-06-09, 19:02 authored by Siân R Kitcher, Nerissa K Kirkwood, Esra D Camci, Patricia Wu, Robin M Gibson, Van A Redila, Roberto Ogelman, Julian A Simon, Edwin W Rubel, David W Raible, Guy Richardson, Corne KrosAminoglycoside (AG) antibiotics are widely used to prevent life-threatening infections, and cisplatin is used in the treatment of various cancers, but both are ototoxic and result in loss of sensory hair cells from the inner ear. ORC-13661 is a new drug that was derived from PROTO-1, a compound first identified as protective in a large-scale screen utilizing hair cells in the lateral line organs of zebrafish larvae. Here, we demonstrate, in zebrafish larvae and in mouse cochlear cultures, that ORC-13661 provides robust protection of hair cells against both ototoxins, the AGs and cisplatin. ORC-13661 also prevents both hearing loss in a dose-dependent manner in rats treated with amikacin and the loading of neomycin-Texas Red into lateral line hair cells. In addition, patch-clamp recordings in mouse cochlear cultures reveal that ORC-13661 is a high-affinity permeant blocker of the mechanoelectrical transducer (MET) channel in outer hair cells, suggesting that it may reduce the toxicity of AGs by directly competing for entry at the level of the MET channel and of cisplatin by a MET-dependent mechanism. ORC-13661 is therefore a promising and versatile protectant that reversibly blocks the hair cell MET channel and operates across multiple species and toxins.
Funding
Mechanisms of aminoglyscoside ototoxicity and drug damage repair in sensory hair cells: towards the design of otoprotective strategies.; G1025; MRC-MEDICAL RESEARCH COUNCIL; MR/K005561/1
History
Publication status
- Published
File Version
- Published version
Journal
JCI InsightISSN
2379-3708Publisher
American Society for Clinical InvestigationExternal DOI
Issue
15Volume
4Page range
1-19Department affiliated with
- Neuroscience Publications
Research groups affiliated with
- Sussex Neuroscience Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2019-09-24First Open Access (FOA) Date
2019-09-24First Compliant Deposit (FCD) Date
2019-09-17Usage metrics
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